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Evaluating the Effectiveness of Cancer Drug Sensitization In Vitro and In Vivo
Published on: February 6, 2015
Development of a high-content screening assay panel to accelerate mechanism of action studies for oncology research
Danli L Towne1, Emily E Nicholl, Kenneth M Comess
1Abbott Laboratories, Global Pharmaceutical Research & Development, Lead Discovery Technologies, Abbott Park, IL 60064, USA.
Abstract:
Efficient elucidation of the biological mechanism of action of novel compounds remains a major bottleneck in the drug discovery process. To address this need in the area of oncology, we report the development of a multiparametric high-content screening assay panel at the level of single cells to dramatically accelerate understanding the mechanism of action of cell growth-inhibiting compounds on a large scale. Our approach is based on measuring 10 established end points associated with mitochondrial apoptosis, cell cycle disruption, DNA damage, and cellular morphological changes in the same experiment, across three multiparametric assays. The data from all of the measurements taken together are expected to help increase our current understanding of target protein functions, constrain the list of possible targets for compounds identified using phenotypic screens, and identify off-target effects. We have also developed novel data visualization and phenotypic classification approaches for detailed interpretation of individual compound effects and navigation of large collections of multiparametric cellular responses. We expect this general approach to be valuable for drug discovery across multiple therapeutic areas.
Insights
We developed a multiparametric assay to rapidly determine how compounds affect cancer cells. This high-content screening method analyzes multiple cellular responses to accelerate drug discovery and understand compound mechanisms of action.
Area of Science:
- Oncology
- Cell Biology
- Drug Discovery
Background:
- Elucidating the biological mechanism of action for novel compounds is a significant challenge in drug discovery.
- Understanding how compounds affect cellular processes is crucial for developing effective cancer therapies.
Purpose of the Study:
- To develop a multiparametric high-content screening assay panel for large-scale analysis of cell growth-inhibiting compounds.
- To accelerate the understanding of compound mechanisms of action in oncology.
Main Methods:
- Developed a single-cell, multiparametric assay panel measuring 10 endpoints.
- Assays assess mitochondrial apoptosis, cell cycle disruption, DNA damage, and morphological changes.
- Utilized novel data visualization and phenotypic classification for detailed interpretation.
Main Results:
- The assay panel enables large-scale, detailed analysis of compound effects on cellular processes.
- Integrated data provides insights into target protein functions and potential off-target effects.
- Facilitates the constraint of possible targets for compounds identified via phenotypic screening.
Conclusions:
- This multiparametric screening approach significantly accelerates the elucidation of compound mechanisms of action.
- The developed assays and analysis tools are valuable for oncology drug discovery.
- The general approach is expected to benefit drug discovery across multiple therapeutic areas.
